Published online Mar 26, 2024.
https://doi.org/10.3802/jgo.2024.35.e76
A retrospective study of dose-dense paclitaxel and carboplatin plus bevacizumab as first-line treatment of advanced epithelial ovarian cancer
,1
Kazuaki Takahashi,1
Hiroshi Tanabe,1,2
Yuichi Shoburu,1
Misato Kamii,1
Akina Tsuda,1
Motoaki Saito,1
Kyosuke Yamada,1
Hirokuni Takano,1
Hirofumi Michimae,3
and Aikou Okamoto1
Abstract
Objective
This study compared the effectiveness, safety, and tolerability of dose-dense paclitaxel and carboplatin plus bevacizumab (ddTC+Bev) with ddTC for advanced ovarian cancer.
Methods
We retrospectively analyzed the clinical records of 134 patients who received ddTC+Bev or ddTC as first-line chemotherapy for stage III–IV ovarian cancer. Progression-free survival as primary endpoint of this study was compared using the log-rank test. Cox proportional hazards model and propensity score matching (PSM) were used to analyze prognostic factors, and the frequency of adverse events was examined using the χ2 test.
Results
We categorized 134 patients in the ddTC+Bev (n=57) and ddTC (n=77) groups who started treatment at four related institutions from November 2013 to December 2017. No patients used poly (ADP-ribose) polymerase inhibitors as the first line maintenance therapy. The progression-free survival (PFS) of the ddTC+Bev group had a significantly better prognosis than that of the ddTC group (hazard ratio [HR]=0.50; 95% confidence interval [CI]=0.32–0.79; p<0.003). Multivariate analysis showed that ddTC+Bev regimen was a prognostic factor. However, intergroup comparison using PSM revealed that the PFS of the ddTC+Bev group had a nonsignificantly better prognosis than that of the ddTC group (HR=0.70; 95% CI=0.41–1.20; p=0.189). Few adverse events above G3 were noted for ddTC+Bev, which were sufficiently tolerable.
Conclusion
This study could not demonstrate that adding Bev to ddTC improves prognosis. Further studies with more cases are warranted.
Synopsis
There are few reports about adding bevacizumab (Bev) to dose-dense paclitaxel and carboplatin (ddTC). We retrospectively examined the efficacy and safety of ddTC+Bev and ddTC. Propensity matching analysis showed that ddTC+Bev did not improve the prognosis in this study.
INTRODUCTION
After the 3rd International Ovarian Cancer Consensus Conference took place in 2004, paclitaxel-carboplatin (TC) became the standard treatment for ovarian cancer worldwide [1]. Subsequently, in the JGOG 3016 trial, which included patients with stage II–IV epithelial ovarian cancer according to the International Federation of Gynecology and Obstetrics (FIGO) classification, it was found that progression-free survival (PFS) and overall survival (OS) were significantly longer with dose-dense paclitaxel and carboplatin (ddTC) than with TC [2, 3, 4]. However, in the ICON8 trial, TC, ddTC, and weekly TC were compared among patients with stage IC–IV epithelial ovarian cancer, and it was found that PFS was not prolonged significantly in the ddTC group [5].
Further, following the introduction of bevacizumab (Bev)—a humanized monoclonal antibody that targets vascular endothelial growth factor and plays an important role in tumor growth by inhibiting angiogenesis—the GOG 218 and ICON7 trials demonstrated that the concurrent use of Bev in TC as the first-line treatment of ovarian cancer prolonged PFS [6, 7]. Bev was allowed at the physician’s discretion in the GOG 262 trial, which examined the effectiveness of ddTC. The subset results revealed that ddTC was effective only in patients who did not concurrently use Bev [8]. These results are only based on a subset analysis, and the effect of ddTC+Bev cannot be ruled out based solely on these results. Therefore, to the best of our knowledge, the effectiveness of the combination of Bev and ddTC has never been examined in randomized controlled trials.
Furthermore, information on the safety of ddTC+Bev was collated in the GOG 262 trial and several single-arm trials. In the GOG 262 trial, no problematic toxic effects due to the combined use of ddTC+Bev were identified [8]. Moreover, in several single-arm trials, it was concluded that the adverse events (AEs) of ddTC+Bev were tolerable [9, 10, 11].
Recently, with the introduction of poly (ADP-ribose) polymerase inhibitors (PARPi), PARPi maintenance therapy following first-line chemotherapy has come into use based on the results of the PRIMA and SOLO-1 trials [12, 13]. The results of the PAOLA-1 trial led to PARPi (olaparib)+Bev becoming one treatment option as maintenance therapy following TC+Bev for patients with homologous recombination deficiency [14]. However, in this study, ddTC was not considered as one of the treatment options.
Based on the circumstances described above as well as the results of the JGOG 3016 study showing that ddTC significantly prolongs PFS and OS compared with TC, it is worth investigating the effectiveness and safety of Bev in combination with ddTC. Therefore, in this study, we aimed to retrospectively examine the efficacy and safety of ddTC+Bev compared with ddTC.
MATERIALS AND METHODS
1. Ethics approval
Approval for this study was obtained from the ethical review board of our institution (31-387[9967]). In accordance with the Ethical Guidelines for Medical Research Involving Human Subjects, we adopted an opt-out approach for the implementation of research, including the purpose of the clinical research concerned.
2. Patient recruitment
We retrospectively investigated patients with stage III–IV epithelial ovarian, fallopian tube, and primary peritoneal cancer who received ddTC+Bev or ddTC as first-line chemotherapy at our four affiliated institutes from November 1, 2013 to December 31, 2017. In contrast, patients who received PARPi as first-line maintenance therapy were not included.
3. Treatment regimen
In both patient groups, paclitaxel and carboplatin were administered in accordance with the protocol mentioned in the JGOG 3016 trial [3].
ddTC+Bev therapy
Paclitaxel (80 mg/m2, days 1, 8, and 15), carboplatin (area under the curve [AUC] 6, day 1), and Bev (15 mg/kg, day 1) were administered every 3 weeks for 6–9 cycles, followed by Bev maintenance therapy. During Bev maintenance therapy, Bev is administered every 3 weeks up to a total of 21 cycles based on the GOG 218 trial [6]. The administration of Bev was discontinued for 4 weeks before and after surgery.
ddTC therapy
Paclitaxel (80 mg/m2, days 1, 8, 15), carboplatin (AUC 6, day 1), and Bev (15 mg/kg, day 1) were administered every 3 weeks for 6–9 cycles.
4. Toxicity monitoring
Weekly blood biochemistry tests and medical examinations were performed in both groups during paclitaxel and carboplatin administration to determine the presence or absence of AE. Furthermore, qualitative analysis of proteinuria was performed as needed. In the Bev maintenance phase of the ddTC+Bev group, evaluations were performed every 3 weeks.
5. Assessment
We retrospectively examined patients’ medical records for age, stage, histological type, surgical completeness, and initial treatment, which are known to contribute to prognosis [15, 16, 17] as well as the details of the currently desired regimen, which was classified into ddTC+Bev or ddTC. The presence or absence of AE was examined. Cancer stage was classified into stage III or IV based on the FIGO 2014 classification [18]. Initial treatment was divided into primary debulking surgery (PDS) or neoadjuvant chemotherapy (NAC) ± interval debulking surgery (IDS). NAC ± IDS included patients who were scheduled for IDS but did not undergo it because of factors, such as symptom exacerbation. Surgical completeness was classified as complete or incomplete, and defined by the final surgical details for the patient, which included the residual tumor diameter after PDS in patients who underwent PDS and the diameter after IDS in patients who underwent NAC. For patients who were unable to undergo the scheduled IDS, the residual tumor diameter at the time of exploratory laparotomy or laparoscopy was used. Cases that were deemed complete by IDS, in the NAC group, were classified as “complete cases,” while those that could not be deemed complete by IDS were classified as “incomplete cases,” in addition to other cases that could not be deemed complete by IDS. Additionally, cases that have not undergone exploratory laparotomy or laparoscopy are also considered “incomplete cases” although, in principle, an exploratory laparotomy is performed before NAC.
Regarding AEs, on the basis of the Common Terminology Criteria for Adverse Events (CTCAE) ver. 4.0, we examined the neutrophil count, hemoglobin levels, platelet count, and the presence or absence of febrile neutropenia as hematotoxicity. Furthermore, the presence or absence of peripheral neuropathy, gastrointestinal symptoms (nausea and vomiting), nephropathy, hypertension, proteinuria, bleeding, thromboembolism, gastrointestinal perforation, and other AEs were examined as nonhematological toxicities.
6. Outcome measure
Primary endpoint
PFS was defined as the primary endpoint. PFS was calculated as the time from the date of PDS or the beginning date of NAC to the day of disease progression or death from any cause. Disease progression was typically diagnosed using imaging or pathological analyses.
Secondary endpoint
Safety evaluation was defined as the secondary endpoint. The AE grade was evaluated using the CTCAE ver.4.0, and the frequency of occurrence of AEs was compared. The ddTC+Bev regimen was further divided into the concurrent chemotherapy phase and the Bev maintenance phase. The frequency of AEs in the ddTC+Bev (concurrent chemotherapy phase) and the ddTC groups was compared, and the incidence of AE in the ddTC+Bev group (maintenance phase) was investigated.
7. Statistical analysis
In the present study, analyses of effectiveness and safety were conducted for all participants and for participants after propensity score matching (PSM). Propensity score-matched patients were those who were selected using nearest-neighbor matching of 1:1 based on the propensity scores after estimating the propensity scores using logistic regression, with the treatment group as the response variable and factors considered to predict prognosis, including age (<60 or ≥60 years), staging, histological type, initial treatment, and surgery completeness as covariates. For an intergroup comparison of patient background factors, continuous variables (follow-up period and age) were examined using the Mann–Whitney U test. Categorical variables, such as age (<60 or ≥60 years), histological type, staging (FIGO 2014), initial treatment, and surgical completeness were examined using the χ2 test. The difference between the 2 groups in terms of patient background factors was calculated as a standardized intergroup difference. To evaluate effectiveness, PFS was compared between the 2 groups using the log-rank test. To estimate the therapeutic outcomes adjusted for prognosticators, we used the Cox proportional hazards model. To examine safety, the incidence of AEs was compared between the two groups using the χ2 test. In the present study, we used SAS ver. 9.4 (SAS Institute Inc., Cary, NC, USA) for propensity score estimation and matching, log-rank tests, and the Cox proportional hazards model. Furthermore, EZR version 1.41 (Saitama Medical Center, Jichi Medical University, Saitama, Japan) was used for other analyses.
RESULTS
1. Patient background
Among 149 patients diagnosed with epithelial ovarian, fallopian tube, and primary peritoneal cancers during the target period, 57 patients received ddTC+Bev and 77 received ddTC (Fig. 1). In the patient background (Table 1), a significant difference was observed in the initial treatment (PDS) (ddTC+Bev group vs. ddTC group: 70.2% vs. 51.9%, p=0.049; standardized difference=0.381) and surgical completeness (complete) (ddTC+Bev group vs. ddTC group: 79.6% vs. 51.9%, p=0.007; standardized difference=0.504); therefore, PSM was performed. Following PSM, there were 44 patients each in the ddTC+Bev and ddTC groups (Fig. 1). In the patient background following PSM, there was no significant difference observed between the 2 groups (Table 1).
Fig. 1
Flowchart of patient inclusion in the study.
Bev, bevacizumab; ddTC, dose-dense paclitaxel and carboplatin; FIGO, International Federation of Gynecology and Obstetrics.
Table 1
Patent characteristics (pre- and post-matching)
2. Efficacy
Before PSM, the univariate analysis revealed that PFS was significantly prolonged in the ddTC+Bev group compared with the ddTC group (median ddTC+Bev group vs. ddTC group: 36 vs. 21 months, p=0.003) (Fig. 2). The multivariate analysis revealed that histological type (serous/endometrioid [S/E] vs. non-S/E: hazard ratio [HR]=0.464; 95% confidence interval [CI]=0.27–0.797), initial treatment (PDS vs. NAC ± IDS: HR=0.552; 95% CI=0.349–0.875), surgical completeness (non-complete vs. complete: HR=3.475; 95% CI=2.14–5.642), and regimen (ddTC+Bev vs. ddTC: HR=0.546; 95% CI=0.334–0.893) were independent prognostic factors (Table 2). After PSM, the univariate analysis revealed no prolongation of PFS (median ddTC+Bev group vs. ddTC group: 27 vs. 22 months, p=0.189) (Fig. 3). The multivariate analysis revealed that surgical completeness (complete vs. non-complete: HR=3.39; 95% CI=1.825–6.296) alone was an independent prognostic factor, whereas regimen (ddTC+Bev vs. ddTC: HR=0.675; 95% CI=0.391–1.166) was not (Table 2).
Fig. 2
PFS curves by product-limit method (pre-matching) according to chemotherapy regimen.
Bev, bevacizumab; ddTC, dose-dense paclitaxel and carboplatin; HR, hazard ratio; PFS, progression-free survival.
Table 2
Cox proportional hazard model of progression-free survival (pre- and post-matching)
Fig. 3
PFS curves by product-limit method (post-matching) according to chemotherapy regimen.
Bev, bevacizumab; ddTC, dose-dense paclitaxel and carboplatin; HR, hazard ratio; PFS, progression-free survival.
3. Safety
We examined the safety of 57 and 77 patients in the ddTC+Bev and ddTC groups before matching. Of the 57 patients receiving ddTC+Bev, 34 patients, including 17 in the concurrent chemotherapy phase and 17 in the Bev maintenance phase, discontinued Bev due to AEs or progression disease, with a Bev discontinuation rate of 59.6%. Throughout the entire period, there were no treatment-related deaths in each group. In the ddTC+Bev group (concurrent chemotherapy phase), AEs (grade 3≤) included neutropenia, anemia, thrombocytopenia, febrile neutropenia, nausea, vomiting, hypertension, proteinuria, and thromboembolism and their percentages were 89.5%, 80.7%, 38.6%, 3.5%, 3.5%, 1.8%, 1.8%, 3.5%, and 1.8%, respectively. There was no peripheral neuropathy, renal dysfunction, bleeding, or gastrointestinal perforation of grade 3 or above observed. The following AEs (grade 3≤) were observed in the ddTC group: neutropenia, anemia, thrombocytopenia, febrile neutropenia, nausea, vomiting, peripheral neuropathy, hypertension, thromboembolism, and gastrointestinal perforation in 74.0%, 64.9%, 32.5%, 5.2%, 1.3%, 1.3%, 1.3%, 1.3%, 1.3%, and 2.6%, respectively (Table 3). Regarding the incidence of AEs (grade 3≤) between the ddTC+Bev (concurrent chemotherapy phase) and the ddTC groups, there was no significant difference observed in the incidence of AEs (data not shown). In patients who transitioned to the Bev maintenance phase, neutropenia was observed in 2.5%, anemia in 7.5%, thrombocytopenia in 5.0%, hypertension in 10.5%, and proteinuria in 17.5% (Table 3).
Table 3
Grade 3/4 adverse events (% of patients)
DISCUSSION
This study revealed that the PFS of the ddTC+Bev group demonstrated a significantly better prognosis than that of the ddTC group (HR=0.502; 95% CI=0.318–0.793; p<0.003). Additionally, the median PFS was significantly more prolonged in the ddTC+Bev group (36 months) than in the ddTC group (21 months). Furthermore, in the Cox proportional hazards model, the regimen was an independent prognostic factor (ddTC+Bev group vs. ddTC group: HR=0.546; 95% CI=0.334–0.893). However, intergroup comparison according to PSM did not show a statistically significant improvement in PFS in the ddTC+Bev group compared with the ddTC group (HR=0.699; 95% CI=0.409–1.195; p=0.189). This discrepancy in results may be attributed to the fact that there was a significant difference between the two groups in terms of initial treatment (PDS) (ddTC+Bev group vs. ddTC group: 70.2% vs. 51.9%, p=0.049; standardized difference=0.381) and surgical completeness (complete) (ddTC+Bev group vs. ddTC group: 75.4% vs. 51.9%, p=0.007; standardized difference=0.504).Before PSM, the ddTC+Bev group included more PDS cases and complete surgery cases, and the intergroup difference between these 2 covariates affected prognosis. It is possible that the statistical power was reduced before and after PSM due to a decrease in the number of patients.
We compared the safety of the ddTC+Bev and ddTC groups and examined the characteristics of AE in the Bev maintenance phase of the ddTC+Bev group. Compared with the ddTC group, the ddTC+Bev group (ddTC concurrent chemotherapy phase) demonstrated no significant difference in the incidence of AEs (grade 3≤). In the JGOG 3016 trial, it was reported that hematotoxicities occur at a high frequency in the ddTC group, whereas nonhematological toxicities occur at a low frequency (1%–10%) [3]. These findings are consistent with those of the present study, and it is thought that AEs may not be a cause for concern by adding Bev to ddTC. In the OCTAVIA trial—a single-arm phase II study evaluating front-line Bev, carboplatin and weekly paclitaxel for ovarian cancer—the frequency of hematotoxicities was lower than that in the present trial and JGOG 3016 trial. Notably, in the OCTAVIA trial, paclitaxel and carboplatin administration criteria were set at higher levels than the administration criteria of the present study and JGOG 3016 trial. In addition, prophylactic filgrastim (granulocyte-colony stimulating factor) and sargamostin (granulocyte macrophage-colony stimulating factor) were proactively administered in the OCTAVIA trial [3, 9].
In the present study, in the Bev maintenance phase of ddTC+Bev, neutropenia was observed in 2.5% (1 patient), anemia in 7.5% (3 patients), and thrombocytopenia in 5.0% (2 patients) patients included in the maintenance phase of ddTC+Bev. In terms of nonhematotoxicities, the incidences of hypertension and proteinuria were higher in the Bev maintenance phase (hypertension, 10.5%; proteinuria, 17.5%) than in the ddTC concurrent chemotherapy phase (hypertension, 1.8%; proteinuria, 3.5%). In the OCTAVIA trial, the incidence of hypertension was 0.5% in the ddTC concurrent chemotherapy phase and 4.8% (elevated) in the Bev maintenance phase. Hypertension was 0.5% in the ddTC concurrent chemotherapy phase and 4.8% (elevated) in the Bev maintenance phase [9]. Safety was examined in the JGOG 3022 prospective trial of continuous Bev monotherapy following concurrent Bev in platinum combination chemotherapy for Japanese patients with advanced ovarian cancer. For all grades, the incidence of hypertension was 54.6%, and the incidence of proteinuria was 47.1%, with an increase in the cumulative incidences over time that reached a plateau approximately 15–18 months after treatment began [19]. Based on the results of the present study, the OCTAVIA trial, and the JGOG 3022 trial, we believe that hypertension and proteinuria should be monitored even after entering the Bev maintenance phase.
As a limitation of AEs, due to the small sample size in our study, the power to detect rare AEs, such as intestinal perforation, is insufficient.
Additionally, this study includes cases from a period when insurance in Japan did not cover PARPi. PARPi has been recently used in treating ovarian cancer, thereby increasing the number of treatment options for ovarian cancer.
New combinations of PARPi with different agents (angiogenesis inhibitors and immune checkpoint inhibitors) in treating ovarian cancer, as well as providing front-line treatment, need to be explored [20]. Future research should include BRCA and homologous recombination deficiency status and should be based on individualized treatment, such as selecting a group of patients to whom Bev should be added or patients who should be treated with ddTC instead of TC in the first place.
In conclusion, the results of the present study demonstrated that adding Bev to dose-dense paclitaxel, carboplatin, might improve the prognosis of advanced ovarian cancer. However, the present study is a retrospective study, and using PSM reduced the number of subjects and statistical power. Research findings on tolerance have been accumulated, and a randomized controlled trial comparing ddTC+Bev to ddTC should be conducted to verify prognostic improvement in the future.
PresentationWe presented the findings of this study at the 72th Annual Congress of the Japan Society of Obstetrics and Gynecology in 2020.
Funding:This research was supported by AstraZeneca K.K., Johnson & Johnson K.K., and Takeda Pharmaceutical Company Ltd.
Conflict of Interest:Aikou Okamoto has honoraria from Takeda Pharmaceutical Company Ltd., AstraZeneca K.K., MSD K.K., Mochida Pharmaceutical Co., Ltd., Bayer Holding Ltd., Kaken Pharmaceutical Co., Ltd., ASKA Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd., Fuji Pharma Co., Ltd., Zeria Pharmaceutical Co., Ltd., Eisai Co., Ltd., and Takeda Pharmaceutical Company Ltd. Also, Dr. Okamoto was supported by research funding from Meiji Holdings Co., Ltd., Fuji Pharma Co., Ltd., Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Kaken Pharmaceutical Co., Ltd., Nippon Shinyaku Co., Ltd., ASKA Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., MSD K.K., Eisai Co., Ltd., Takeda Pharmaceutical Company Ltd., Mochida Pharmaceutical Co., Ltd, Linical Co., Ltd., Pfizer Japan Inc., Gyne Mom Co.Ltd, Terumo Corporation, Kissei Pharmaceutical Co., Ltd., AstraZeneca K.K., Tsumura & Co., and Daiichi Sankyo Co., Ltd.
The other authors have no conflicts of interest directly relevant to the contents of this article.
Author Contributions:
Conceptualization: K.H., T.K., 1T.H., O.A.
Data curation: K.H., S.Y., K.M., T.A., S.M., Y.K., 2T.H.
Formal analysis: K.H., T.K., 1T.H., M.H.
Funding acquisition: O.A.
Supervision: 1T.H., O.A.
Writing - original draft: K.H., T.K., 1T.H.
Writing - review & editing: K.H., T.K., 1T.H.
1T.H., Hiroshi Tanabe; 2T.H., Hirokuni Takano
ACKNOWLEDGEMENTS
We thank a member of the Obstetrics and Gynecology Department, School of Medicine, Jikei University, for discussion on this study.
References
-
du Bois A, Quinn M, Thigpen T, Vermorken J, Avall-Lundqvist E, Bookman M, et al. 2004 consensus statements on the management of ovarian cancer: final document of the 3rd International Gynecologic Cancer Intergroup Ovarian Cancer Consensus Conference (GCIG OCCC 2004). Ann Oncol 2005;16 Suppl 8:v1117–v1112.
-
-
Katsumata N, Yasuda M, Isonishi S, Takahashi F, Michimae H, Kimura E, et al. Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): a randomised, controlled, open-label trial. Lancet Oncol 2013;14:1020–1026.
-
-
Harano K, Terauchi F, Katsumata N, Takahashi F, Yasuda M, Takakura S, et al. Quality-of-life outcomes from a randomized phase III trial of dose-dense weekly paclitaxel and carboplatin compared with conventional paclitaxel and carboplatin as a first-line treatment for stage II-IV ovarian cancer: Japanese Gynecologic Oncology Group Trial (JGOG3016). Ann Oncol 2014;25:251–257.
-
-
Clamp AR, James EC, McNeish IA, Dean A, Kim JW, O’Donnell DM, et al. Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal carcinoma treatment (ICON8): primary progression free survival analysis results from a GCIG phase 3 randomised controlled trial. Lancet 2019;394:2084–2095.
-
-
González-Martín A, Pothuri B, Vergote I, DePont Christensen R, Graybill W, Mirza MR, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 2019;381:2391–2402.
-
-
Roett MA, Evans P. Ovarian cancer: an overview. Am Fam Physician 2009;80:609–616.
-
-
Komiyama S, Kato K, Inokuchi Y, Takano H, Matsumoto T, Hongo A, et al. Bevacizumab combined with platinum-taxane chemotherapy as first-line treatment for advanced ovarian cancer: a prospective observational study of safety and efficacy in Japanese patients (JGOG3022 trial). Int J Clin Oncol 2019;24:103–114.
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